Compositions and methods for treating diseases of the nail

ABSTRACT

Methods and compositions for treating disorders of the nail and nail bed. Such compositions contain a vehicle in which all components of the composition are dissolved, suspended, dispersed, or emulsified, a non-volatile solvent, a wetting agent, and a pharmaceutically active ingredient that is soluble in the non-volatile solvent and/or a mixture of the vehicle and the non-volatile solvent, and which composition is effective in treating a disorder of the nail or nail bed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. application Ser. No.12/006,531, filed Jan. 8, 2008, which is hereby incorporated byreference for all purposes.

FIELD OF THE INVENTION

The invention pertains to the field of treatment of diseases of the nailand nail bed. In particular, the invention pertains to methods fortreatment of disorders such as onychomycosis or psoriasis involving thenails.

BACKGROUND OF THE INVENTION

Onychomycosis, a fungal disease of the nail unit caused by yeasts,dermatophytes, or other molds, accounts for approximately 50% of allnail disorders in humans. In about 80% of onychomycosis cases, thetoenails are infected, whereas in the remaining 20%, the fingernails areinfected. The symptoms of this disease include split, thickened,hardened, and rough nail plates.

Another common disorder of nails is nail psoriasis, which affects up to50% of patients with psoriasis. Characteristic nail psoriasis symptomsinclude pitting, which appears as punctuated or irregularly shapeddepressions arranged on the surface of the body of the nail;discoloration of the nail bed; onycholysis or detachment of the body ofthe nail from the nail bed; subungual keratosis; or anomalies of thebody of the nail. Other diseases and disorders involving the nails inhumans and in other animals include onychia, onychocryptosis,onychodystrophy, onychogryposis, onycholysis, onychomadesis,onychophosis, onychoptosis, paronychia, koilonychia, subungual hematoma,and laminitis.

The nail plate is thick, hard, and dense, and represents a formidablebarrier to drug penetration. Although nail material is similar invarious ways to the stratum corneum of the skin, the nail is composedprimarily of hard keratin which is highly disulfide-linked and isapproximately 100-fold thicker than stratum corneum.

Various topical therapies have been suggested for treatment of naildisorders, such as onychomycosis. Nail lacquers, coating, polishes,enamels, and varnishes have been described. Bohn, U.S. Pat. No.4.957,730, describes a nail varnish containing a water-insolublefilm-forming substance and antimycotic compound. Ferro, U.S. Pat. No.5,120,530, describes an antimycotic nail varnish containing amorolfinein quaternary ammonium acrylic copolymer. The water-insoluble filmformer is a copolymerizate of acrylic acid esters and methacrylic acidesters having a low content of quaternary ammonium groups. Bohn, U.S.Pat. No. 5,264,206, describes a nail lacquer with antimycotic activity,which contains an antimycotic agent and water-insoluble film formersincluding polyvinyl acetate, a copolymer of polyvinyl acetate andacrylic acid, copolymers of vinyl acetate and crotonic acid. Wohlrab,U.S. Pat. No. 5,346,692, describes a nail lacquer for treatingonychomycosis, comprised of a film-forming agent, an antimycoticallyactive substance, and urea, wherewith the antimycotic agent and urea areliberated from the lacquer when the lacquer is applied. A preferredformulation comprises cellulose derivatives as film former, clotrimazoleas the antimycotic agent, dibutyl phthalate as a plasticizer, and amixture of acetone and ethanol as solvent. Nimni, U.S. Pat. No5,487,776, describes a nail lacquer composition which forms a waterpermeable film containing griseofulvin when the organic solvent systemevaporates, wherein a portion of the griseofulvin is in solution and aportion of griseofulvin is present as a colloidal suspension. Chaudhuri,U.S. Pat. No. 6,143,794, describes a topical formulation for thetreatment of nail fungal infections that includes an antifungal,solvent, gelling agent, adhesion-promoting agent, film-forming agent,surfactant, and optionally a keratolytic agent. The adhesion-promotingagent was a hydroxy-terminated polyurethane such as polyolprepolymer-2.All of these patents and publications describe products applied to thenail that form a substantive nail coating or film containing a drug fromwhich the drug is to penetrate into the nail. None of these methods hasproven to be consistently effective in treating disorders of the nailsuch as onychomycosis.

Various topical therapies utilizing chemical compounds disclosed toenhance penetration through the nail have been described. Knowles, U.S.Pat. No. 5,652,256, describes the use of methyl acetate as a penetrationenhancing compound in combination with naftifine or sulconazole andnaftifine as a topical gel for fungal treatment of the nails. Sorenson,U.S. Pat. No. 5,972,317, discloses that a proteolytic enzyme such aspapain, delivered by pads soaked in the enzyme solution, produces a morepermeable nail. Sun, U.S. Pat. No. 6,231,875, describes acidifiedcompositions of antifungals to enhance transport across nails and skin.Reeves, U.S. Pat. No. 6,391,879, describes the combination of ananti-fungal agent dissolved in an anhydrous blend of polyglycol andDMSO. Although these and other enhanced penetration formulations werereported to increase penetration through the nail, they have not beenshown to be clinically effective in treating conditions of the nail,such as onychomycosis.

Because of the difficulty in obtaining clinically effectiveconcentrations of medication to the nail bed by topical application of apharmaceutical composition to the affected nail, nail disorders, such asonychomycosis, are typically treated with systemic medications or withtopical medications following removal of the nail. Systemic treatmentfor onychomycosis and other nail disorders is often not satisfactorybecause therapy must be continued for long periods of time, often manyweeks or months, and the medication has effects on tissues other than onthe affected nail. Antifungal compounds, such as miconazole andketoconazole, have been demonstrated to be effective in topicallytreating onychomycosis after nail removal. However, it is clear thatremoval of the nail is a measure than most individuals suffering fromonychomycosis would prefer not to undergo if a less drastic therapeuticmethod would be efficacious.

Pitre, U.S. Patent Publication 2007/0041910, filed as U. S. patentapplication Ser. No. 11/432,410; and Mallard, U.S. Patent Publication2006/0147383, filed as U.S. patent application Ser. No. 11/315,259,disclose that application of a pharmaceutical composition containing avehicle, a volatile silicone, and a non-volatile oily phase, providesincreased penetration of a pharmaceutically active compound whentopically to skin or mucous membrane. This enhanced penetration isobtained without the use of glycols, such as propylene glycol, which areknown to augment skin penetration of pharmaceutical compounds but whichare also known to be irritating to skin. The formulations of Pitre andMallard contain at least 25% w/w of a volatile silicone and, ifformulated with an alcoholic vehicle, contain at least 15% of alcohol.All alcoholic compositions disclosed in Pitre and Mallard containgreater than 50% volatile silicone and the concentration of the volatilesilicone is at least twice the concentration of the alcohol in thecomposition.

Pitre and Mallard do not disclose or suggest the use of suchcompositions for the treatment of diseases of a nail, such asonychomycosis. Moreover, studies have been conducted, including studiesconducted in the laboratories of the present inventors, that show thatthe penetrating ability of an active agent from a composition into skincannot be correlated to the penetrating ability of the active agent fromthe composition into or through a nail.

A significant need remains for a pharmaceutical composition thatprovides for enhanced penetration of a pharmaceutical agent containedwithin the composition into and through an intact nail. Such acomposition would be valuable for topically treating conditionsaffecting the nail or nail bed, such as onychomycosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the in vitro penetration of KP-103 throughskin from a formulation of the invention and from three prior artformulations.

FIG. 2 is a graph showing the in vitro penetration of KP-103 throughnail tissue from a formulation of the invention and from three prior artformulations.

DESCRIPTION OF THE INVENTION

It has been unexpectedly discovered that a pharmaceutical compositioncontaining an active pharmaceutical ingredient (API), a solvent,referred to herein as the “vehicle” or the “volatile vehicle”, a wettingagent which may or may not be the same compound as the vehicle, and anon-volatile solvent which has limited water miscibility providesenhanced penetration of the API into and through an intact nail.Preferably, the composition of the invention is free of film formingpolymeric compounds. It is conceived that such compositions may be usedto deliver an API in order to treat medical conditions involving thenail and/or the underlying nail bed.

In one embodiment, the invention is a pharmaceutical composition for thetreatment of disorders of the nail or nail bed. The pharmaceuticalcomposition of the invention contains a volatile and/or penetratingvehicle, a non-volatile solvent that is dissolved, suspended, dispersed,or emulsified within the vehicle, an API that is soluble in thenon-volatile solvent and/or a mixture of the vehicle and thenon-volatile solvent and is optionally soluble in the vehicle, and awetting agent, which may or may not be the vehicle itself.

In another embodiment, the invention is a pharmaceutical formulation fordelivery of an API to the nail or nail bed in order to treat disordersof this area. According to this embodiment, the formulation contains avolatile and/or penetrating vehicle, a non-volatile solvent that isdissolved, suspended, dispersed, or emulsified within the vehicle, and awetting agent, which may or may not be the vehicle itself. The API thatis to be used with the formulation of the invention is one that issoluble in the non-volatile solvent and/or a mixture of the vehicle andthe non-volatile solvent and is optionally soluble in the vehicle alone.

In another embodiment, the invention is a method for treating a disorderof the nail or nail bed. According to this embodiment of the invention,a pharmaceutical composition containing a volatile and/or penetratingvehicle, a non-volatile solvent that is dissolved, suspended, dispersed,or emulsified within the vehicle, an API that is soluble in thenon-volatile solvent and/or a mixture of the vehicle and thenon-volatile solvent and is optionally soluble in the vehicle alone, anda wetting agent, which may or may not be the vehicle itself, istopically applied to the surface of a nail that is suffering from adisorder in an amount and for a time sufficient to ameliorate thesymptoms of the disorder.

As used herein, the term “volatile” when referring to the vehicle meansthat the vehicle is a compound that evaporates from the surface of thenail when applied. Volatile vehicles are compounds which have ameasurable vapor pressure, and preferably are compounds that have avapor pressure of greater than 100 Pa at room temperature. Examples ofvolatile vehicles include: acetone, 2-amino-2-methyl-1-propanol,1,2-butanediol, 1,4-butanediol, 2-butanol, cyclomethicone-4,cyclomethicone-5, cyclomethicone-6, ethanol, ethyl acetate, n-heptane,isobutanol, isopropyl alcohol, 1-propanol and 2-propanol.

As used herein, the term “penetrating” when referring to the vehiclemeans that the vehicle is a compound that rapidly penetrates into a nailwhen applied to the surface of the nail so that, after 10 minutesfollowing the application of a thin layer of the vehicle onto thesurface of a nail, no more than 10% of the applied amount remains on thenail surface. The term “penetrating” thus includes both volatile andnon-volatile vehicles.

Examples of pharmaceutical compositions that may be used in the methodof the present invention are disclosed in Pitre, U.S. patent applicationSer. No. 11/432,410; and in Mallard, U.S. patent application Ser. No.11/315,259, which applications are incorporated herein in theirentirety. In accordance with the present invention, the pharmaceuticalcompositions of Pitre and Mallard that may be used to treat medicalconditions of the nail in accordance with the present invention maycontain Vitamin D as the API as disclosed in Pitre or clobetasol asdisclosed in Mallard, or may contain other APIs in place of, or inaddition to, these APIs, as disclosed herein.

The API of the composition of the invention is one that is useful in thetreatment of a disorder of the nail or nail bed. The API is soluble inthe solvent of the composition and/or in the combination of the solventand vehicle of the composition. Examples of suitable APIs includeanti-inflammatory agents, antimicrobial agents such as antibiotics andantifungal agents, anesthetic agents, steroidal agents, vitamins andderivatives thereof, anti-psoriatic drugs, and analgesic agents.

In a preferred embodiment, the API of the composition of the inventionis an antifungal chemical compound, particularly those effective in thetreatment of onychomycosis. Examples of suitable antifungal agentsinclude polyene antimycotic agents such as natamycin, rimocidin,filipin, nystatin, and amphotericin B; imidazole compounds such asmiconazole, ketoconazole, clotrimazole, econazole, bifonazole,butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole,suconazole, and tioconazole; triazole compounds such as fluconazole,itraconazole, ravuconazole, posaconazole, voriconazole,(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol(referred to herein as “KP-103”), and terconazole; allylamine compoundssuch as terbinafine, amorolfine, naftifine, and butenafine; echinocandincompounds such as anidulafungin, caspfungin, and micafungin; and otherantifungal drugs such as ciclopirox, flucytosine, griseofulvin, gentianviolet, haloprogin, tolnaftate, and undecylenic acid. Any antifungalcompound suitable for pharmaceutical use in humans or mammals, andparticularly those which are active in vitro against Candida albicans,Trichophyton rubrum or Trichophyton mentagrophytes, is suitable for theAPI of the invention. Particularly preferred are antifungal APIs thathave relatively low binding to keratin, such as triazole compounds likeKP-103.

Other APIs that are suitable for the composition of the inventioninclude those that are effective in treating diseases and disorders ofnails other than onychomycosis, especially those diseases and disordersaffecting tissues deep to the external surface of the nail, such as theinternal portion of the nail, the deep nail surface adjacent to the nailbed, and the nail bed. Such diseases and disorders may include onychia,onychocryptosis, onychodystrophy, onychogryposis, onycholysis,onychomadesis, onychophosis, onychoptosis, paronychia, koilonychia,subungual hematoma, and laminitis.

The vehicle of the composition of the invention is a pharmaceuticallyacceptable vehicle in which the constituents of the composition of theinvention can be dissolved, suspended, disbursed, or emulsified. Theconstituents of the composition may be all within a single phase in thevehicle. For example, the API, wetting agent, and the non-volatile phasemay be dissolved in the vehicle. Alternatively, the constituents mayoccupy separate phases within the vehicle. For example, the API may bedissolved in the vehicle and the other constituents may be suspended,dispersed, or emulsified in solvent. For another example, the API may bedissolved in the solvent which is suspended, dispersed, or emulsified inthe vehicles, with the remaining constituents being dissolved in eitherthe vehicle or the solvent. Preferably, but not necessarily, the API,wetting agent, and non-volatile phase are all miscible in the vehicle.

Examples of suitable vehicles include one or more of water, alcohols,polyols, ethers, esters, aldehydes, ketones, fatty acids, fattyalcohols, and fatty esters. Specific examples of suitable vehiclesinclude ethanol; 3-propanediol; 1,2-butanediol;1,2,3-propanetriol;1,3-butanediol; 1,4-butanediol; isopropyl alcohol;and 2-amino-2-methyl-1-propanol. In a preferred embodiment, the vehicleis an alcohol, and most preferably a linear or branched aliphatic loweralcohol, such as methanol, ethanol, propanol, or isopropanol.

The wetting agent of the composition of the invention is a chemicalcompound that reduces the surface tension of liquid compositions andthat does not build viscosity. The wetting agent may be a surfactant,which may be anionic, cationic, or non-ionic.

Preferably, the wetting agent is a volatile silicone. Such volatilesilicones include linear or cyclic polyorganosiloxane compounds offormula [R₁SiOR₂]_(n) wherein n=6 or less and R₁ and R₂ are alkyl groupsthat may be the same or different, and which compound has a measurablevapor pressure under ambient conditions. Preferably, n=from 3 to 6, andmost preferably n=4 or 5. Preferably R₁ and R₂=methyl.

Examples of cyclic volatile silicones includepolydimethylcyclosiloxanes, generally known as cyclomethicones.Particular examples of cyclic volatile silicones includecyclopentasiloxane, cyclotetrasiloxane, decylmethylcyclopentasiloxane,and octylmethylcyclotetrasiloxane. Examples of linear volatile siliconesinclude linear polysiloxanes. Particular examples of linear volatilesilicones include hexamethyldisiloxane, octamethyltrisiloxane, anddimethicones.

In one particular embodiment of the invention, a single compound formsboth the vehicle and the wetting agent of the composition. For example,the vehicle may be a volatile silicone. In this situation, the volatilesilicone may also be the wetting agent of the composition. In the casein which the wetting agent serves also as the vehicle, the concentrationof the wetting agent in the composition is sufficiently high to functionas a vehicle in which all other components of the composition aredissolved, suspended, dispersed, or emulsified.

The non-volatile solvent of the composition is a non-aqueous solventthat may or may not be soluble or miscible in the vehicle of thecomposition. The API of the composition is preferably, but notnecessarily, soluble in the non-volatile solvent. In a preferredembodiment wherein the API is hydrophilic, the non-volatile solvent is apolar or semi-polar molecule. In another preferred embodiment whereinthe API is hydrophobic, the non-volatile solvent is non-polar.

Suitable non-volatile solvents for hydrophobic drugs are disclosed inPitre, U.S. patent application Ser. No. 11/432,410 in paragraphs 0069 to0082, which paragraphs are incorporated herein by reference. Forexample, the non-volatile solvent may be an ester of the formulaRCO—OR′, wherein R and R′ may be identical or different and each of Rand R′ represents a linear or branched chain of an alkyl, alkenyl,alkoxycarbonylalkyl, or alkoxycarbonyloxyalkyl radical having from 1 to25 carbon atoms, preferably from 4 to 20 carbon atoms. The non-volatilesolvent may be a glyceryl ester of a fatty acid, such as fatty esters ofnatural fatty acids or triglycerides of animal or plant origin. Thenon-volatile solvent may be a fatty acid glyceride, including syntheticor semi-synthetic glyceryl esters, such as fatty acid mono-, di-, ortriglycerides, which are oils or fats. The non-volatile solvent may be anon-volatile hydrocarbon, such as paraffins, isoparaffins, and mineraloil. The non-volatile solvent may be a guerbet ester. The non-volatilesolvent may be a non-volatile silicone, provided that the presence ofthe non-volatile silicone in the composition does not result in theformation of a hard polymeric film upon application of the compositiononto a nail. Included within such non-film forming silicones arepolyorganosiloxane compounds that have the formula [R₁SiOR₂]_(n) whereinn>6 and R₁ and R₂ are alkyl groups that may be the same or different,and which compound may or may not have a measurable vapor pressure underambient conditions.

Other examples of suitable non-volatile solvents for hydrophobic drugsin addition to those disclosed in Pitre include squalane, dibutylsebacate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl strearate, myristyl alcohol, oleyl alcohol, oleic acid, lauryllactate, myristyl lactate, mixed C12-15 alkyl lactates, diisopropyladipate, octyldodecanol, caproic acid, caprylic acid, capric acid,lauryl benzoate, myristyl benzoate, mixed C12 15 alkyl benzoates, benzylbenzoate, tridecyl neopentanoate, spermaceti, petrolatum, and alphaterpineol. Examples of suitable non-volatile solvents for hydrophilicdrugs include diethylene glycol monoethyl ether, n-methyl pyrrolidone,dimethyl sulfoxide, ethyl lactate, hexylene glycol, glycerol, benzylalcohol and glycerol triacetate.

The composition of the invention may contain additional optionalcomponents, such as wetting agents, preservatives, stabilizers,lubricants, humectants, moisture regulators, foaming agents, binders, pHregulators, osmotic pressure modifiers, emulsifiers, antioxidants,colors, fragrances, or odor maskers. If desired, the composition mayalso contain additional nail modifiers or penetration enhancers, such asurea, propylene glycol, sodium lauryl sulfate, and glycolic acid.

The composition is intended to remain in a liquid or semi-solid stateafter application to the nail and does not form a hard lacquer, shell,or film on the nail following application, which occurs by a process ofsolvent casting following evaporation of a volatile solvent which leavesbehind a solid residue that forms the lacquer, shell or film. Therefore,it is preferred that the components of the composition are miscible inthe composition and also are miscible in the “secondary” compositionthat remains after the volatile vehicle has evaporated or penetrated thenail. It is also suitable for the components of the composition, otherthan the vehicle, to be suspendible, dispersible, or emulsifiable, inthe secondary composition, such as in the non-volatile solvent.

The composition of the invention may be prepared in any number of forms,such as ointments, creams, milks, salves, impregnated pads, solutions,tinctures, liniments, liquids, sprays, foams, suspensions, lotions, orpatches. The composition may be formulated to provide for immediate orcontrolled release of the API from the composition.

The concentration of the various essential and optional components ofthe composition of the invention will vary, depending on the particularcomponents contained in the composition, the form of the composition,the particular disease or condition that is to be treated with thecomposition, and whether the formulation is for immediate or forcontrolled release.

The API of the composition is at a concentration that is effective totreat a disorder or disease of the nail or nail bed. Typically, theconcentration of the API will constitute between 0.0001 to 30% or higherby weight of the composition.

The concentration of the wetting agent in the composition may varydepending on several factors, including the identity of the wettingagent and whether the wetting agent is also the vehicle of thecomposition. Generally, the concentration of the wetting agent, such asa volatile silicone, will be between 0.001% to 95% by weight of thecomposition. Preferably, the concentration of the wetting agent isbetween 5% and 80%, more preferably between 7% and 60%, and mostpreferably between 10% and 40% w/w of the composition. In a particularlypreferred embodiment, the concentration of wetting agent in thecomposition is between 10% and 15% w/w. In the case where the wettingagent is not functioning as a vehicle of the composition, theconcentration of wetting agent in the composition will generally betowards the lower end of the above range of concentration, such asbetween 0.001% and 10%.

The concentration of the non-volatile solvent will constitute between 5and 90% w/w of the composition. Generally, with less viscous forms ofthe compositions, lower concentrations of non-volatile phase will bepresent, and with more viscous forms, higher concentrations of thenon-volatile phase will be used. Also, ointment and other predominatelyoil-based compositions tend to have a higher concentration ofnon-volatile phase or components than do compositions such as sprays,gels, and lotions and so will have a higher concentration of anon-volatile solvent. Typical concentrations of non-volatile solvent arebetween 10 and 80%, with preferred concentrations being between 12 and60%, and most preferred concentrations between 15 and 50% w/w.

The concentration of the vehicle will be that which is sufficient todissolve, suspend, disperse, or emulsify the other components of thecomposition. In many but not all cases, the concentration of the vehiclewill be higher than that of any other constituent of the composition. Insome cases, the concentration of the vehicle will be higher than that ofthe combined concentration of the other constituents of the composition.In a preferred embodiment in which the vehicle is an alcohol, thecomposition will contain at least 10% alcohol, more typically at least15% alcohol, and most typically at least 25% alcohol. The concentrationof alcohol in the composition may be as high as 80%, or higher. In onepreferred embodiment, the concentration of alcohol is at least 50% w/wof the composition.

In a particularly preferred embodiment of the invention, the compositionof the invention is an alcoholic composition containing a volatilesilicone. In a first preferred embodiment, the ratio of alcohol tovolatile silicone in the composition % w/w is at least 2:3, preferablyat least 1:1, more preferably at least 2:1, and most preferably at least3:1. In a second preferred embodiment, the concentration of the volatilesilicone in the composition is less than 25% w/w. In a third preferredembodiment, the concentration of the alcohol in the composition is atleast 40%, more preferably at least 45%, and most preferably at least50% w/w. The composition of the invention, according to this embodimentof the invention, may be made so as to encompass any one, two, or allthree of the embodiments described above. It has been determined that,when applied to the surface of a nail, the alcoholic composition of theinvention containing a volatile silicone provides a high degree ofpenetration of an API contained therein into the nail.

Although the compositions of the invention may be used to treat variousdiseases and disorders of the skin or mucous membranes, they are mostadvantageously used to treat conditions involving the nails of the handsor feet. The compositions and methods of the invention provide increasedpenetration of API in the composition into and through the nail and tothe nail bed. The compositions of the invention may be used effectivelyto treat diseases and disorders in humans or in other animals, such ascats, dogs, horses, cattle, sheep, goats, pigs, and birds. In human andin veterinary patients, the compositions of the invention may be used,depending on the particular animal treated, to treat conditionsinvolving nails, hooves, horns, or beaks.

The compositions of the invention are especially well suited for thetreatment of onychomycosis and other disorders of the nail and nail bed.The composition is topically applied to the surface of the nail andsurrounding tissue by any means by which the composition may be applied.The method of application may vary depending on the physical state ofthe composition, whether it is in a liquid, semisolid, or solid form,and on the viscosity of the composition if it is a liquid. Thus, forexample, the composition may be rubbed, painted, dabbed, dripped,sprayed, wiped, spread, or poured onto the affected nail and surroundingtissues, or utilized as a soak. Frequency of treatment and duration oftherapy will very depending on several factors, including the conditionthat is being treated, the identity and concentration of the API in thecomposition, and constituents of the composition other than the API.Typically, the frequency of treatment will be twice daily to onceweekly, and preferably once daily.

To further illustrate the invention, the following examples areprovided. It is to be understood that these examples are provided forillustrative purposes and are not to be construed as limiting the scopeof the invention.

EXAMPLE 1 Skin Penetration Study

Four different formulations were tested to determine the penetrabilityof an API into skin. The formulations each contained 5.00% w/w of atriazole antifungal API compound, KP-103. The compositions of the fourformulations are shown in Table 1. All concentrations of the componentsof the formulations are in % w/w.

TABLE 1 Formulation No. 078 080 082 107 KP-103 5.00  5.00  5.00 5.00alcohol 19.35 20.00  59.998 — triacetin 15.00 — — — glycerin 35.00 24.998 — — 1,3-butylene glycol 25.00 — — — carbomer 980 0.50 — — —diisopropanolamine 0.10 — — — Vitamin E 0.05  0.002  0.002 0.05propylene glycol — 50.00 — — cyclomethicone — — 13.00 — diisopropyladipate — — 12.00 8.20 myristyl lactate — — 10.00 — isopropyl myristate— — — 5.48 white petrolatum — — — 51.27  urea — — — 30.00 

Each of the formulations of Table 1 were spiked with tracer amounts ofradiolabeled KP-103 at approximately 0.90 μCi/dose. A single clinicallyrelevant dose (5 mg/cm2) was applied to dermatomed human skin obtainedfrom one donor following elective surgery.

Percutaneous absorption was evaluated by mounting the dermatomed tissuein Bronaugh flow-through diffusion cells at 32 C. Six replicates wereperformed for each formulation. Fresh receptor fluid, PBS containing0.1% w/v sodium azide and 1.5% Oleth-20, was continuously pumped underthe skin at a nominal flow rate of 1 ml/hr and collected in 6-hourintervals. Following 24-hours of exposure, the residual formulationremaining on the skin surface was removed by repeated tape stripping (5strips/cell). Subsequently, the epidermis was physically separated fromthe dermis by gentle peeling. The quantity of radioactivity in thetape-strips, epidermis, dermis, and receptor fluid samples wasdetermined using liquid scintillation counting. The results for thecalculated quantity of API collected in the receptor for each of theformulations of Table 1 are shown in FIG. 1.

As shown in FIG. 1, Formulations 080 and 107 demonstrated considerablyhigher skin penetration than did Formulations 078 and 082. Formulation080 contains propylene glycol, a known skin-penetration enhancer, andexhibited a higher penetration through skin than any of the otherformulations. Formulation 107 contains urea, a known skin-penetrationenhancer, and exhibited the second highest skin penetration of the fourformulations tested. Formulation 082 is a formulation according to thepresent invention and exhibited the lowest skin penetration of thetested formulations. Formulation 078 is a composition that is not withinthe scope of the invention and exhibited slightly higher penetrationinto and through skin than did Formulation 082. Of the fourformulations, the formulation with the lowest level of skin penetrationwas formulation 082, the only formulation of the four that is acomposition of the invention.

EXAMPLE 2 Nail Penetration Study

The formulations 078, 080, 082, and 107 of Example 1 were tested todetermine penetration of the API from the formulation into and throughnail plates. Each of the formulations of Table 1 was spiked with traceramounts of radiolabeled KP-103 at approximately 0.90 μCi/dose. Aclinically relevant protocol was followed, which entailed dosing 10μL/cm² per day for 14 days onto healthy human finger nail plates, whichwere obtained from multiple donors.

Nail penetration was evaluated by mounting the finger nail plates intocustom diffusion cells. Five replicates were performed for eachformulation. A small cotton ball wetted with 0.1 mL normal saline wasused as a receptor. For each day of the study, the surface of the nailwas washed, and 10 μL of formulation was applied to the surface. Everysecond day, the cotton ball receptor was replaced. After fourteen daysof exposure, the nail plate was sectioned into three sections, a centraldorsal (upper) section, central ventral (lower) section and theremaining peripheral material. The quantity of radioactivity in thedaily surface washes, cotton ball receptors, dorsal nail, ventral nailand peripheral nail was determined using liquid scintillation counting.

The results are shown in FIG. 2. As shown in FIG. 2, the formulation ofthe invention, Formulation 082, provided over 6 times the penetrationthrough the nail and into the saturated cotton ball receptor than didthe other formulations, calculated as a percentage of the applied dose.The penetration of Formulations 080 and 107 had been expected to behighest through nail because they had exhibited a significantly higherpenetration through skin. However, the penetration of API fromFormulations 080 and 107 was, in fact, lower than from the otherformulations even though these Formulations 080 and 107 contained wellknown skin penetration enhancers. This study establishes that thepenetration of API from a formulation through skin is not predictive ofthe penetration of the API from the formulation through nail tissue.This study further establishes the unexpected ability of a preferredformulation of the invention, Formulation 082, to increase thepenetration of API within the formulation through nail tissue.

EXAMPLE 3 Clinical Assessment in Animal Model of Onychomycosis

The efficacy of a formulation of the invention, Formulation 087,containing 3.00% w/w of a triazole antifungal API, KP-103, was evaluatedin an animal model of onychomycosis and, in two separate studies, wascompared with that of several commercial products intended for thetreatment of onychomycosis. The composition of Formulation 087 is shownin Table 2.

TABLE 2 FORMULATION 087 Component Concentration (% w/w) KP-103 3.00Alcohol 60.00 Vitamin E 0.002 Cyclomethicone 13.00 Diisopropyl adipate10.00 Myristyl lactate 13.998

In order to test the efficacy of Formulation 087 and the comparisonproducts, onychomycosis was induced in six-week old Hartley guinea pigs.Each of Formulation 087 and the comparison products were tested in fiveanimals. Two hundred (200) μL of a suspension of Trichophytonmentagrophytes SM-110 (1_10⁸ arthrospores/mL) was inoculated to theplantar and interdigital skin of the hind paws, and the entire feet werethen covered with bandage. The bandage was removed 28 days after fungalinoculation. Test treatments were applied for a period of 30 days,starting on the 60th day after infection.

The infected nails were removed from the feet 7 days following the finaltreatment and were minced with scissors. The nails were placed in aglass homogenizer and PBS (phosphate buffer solution) containing 0.25%porcine pancreatic trypsin was added at a rate of 1 mL/50 mg of wet nailweight, and the nail was homogenized. The homogenate was allowed tostand at 37_C for 1 hour. One hundred microliters of the nail homogenateor its dilution was spread on a GPLP agar medium containing antibioticsand cultured at 30_C for 7 days. After culturing, the fungal coloniesthat appeared on the medium were counted, and the number of colonyforming units (CFU) of fungi in the nails was calculated. The nailsample was considered culture-negative when no fungal colony appeared onthe plate.

In Study 1, the efficacy of Formulation 087, applied to the nails at 30μL/foot once a day for 30 days, was compared with untreated controlanimals and with 5% Amorolfine lacquer (Loceryl®) applied to the nailsat 30 μL/foot once a week for 30 days. In Study 2, 1% naftifine gel(Naftin®) and 8% ciclopirox lacquer (Penlac®), each applied to the nailsat 30 μL/foot once a day for 30 days, were compared with untreatedcontrol animals. The results of Study 1 and Study 2 are shown in Table3.

TABLE 3 No. of feet with culture- Mean no. of CFU negative nails/ innails/foot after total no. of feet Treatment treatment (Log 10) (%)after treatment Study 1 Control (no treatment) 29512 (4.47 +/− 0.37) N/A5% Amorolfine lacquer 2398 (3.38 +/− 0.87) 0/10 (0%)  (Loceryl ®)Formulation 087 63 (1.80 +/− 0.53) 6/10 (60%) Study 2 Control (notreatment) 10964 (4.04 +/− 0.69) N/A 1% Ciclopirox lacquer 214 (2.33 +/−1.10) 1/10 (10%) (Penlac ®) 1% Naftifine gel 501 (2.70 +/− 1.45) 1/10(10%) (Naftin ®)

The data of Table 3 establishes that the formulation of the inventionwas more efficacious in treating onychomycosis in an animal model ofhuman disease than were several currently available therapies foronychomycosis. With Formulation 087 of the invention, 60% of theinfected nails were culture-negative following treatment. With thecompositions of the prior art, 10% or less of the infected nails wereculture-negative following treatment.

EXAMPLE 4 Clinical Assessment in Human Treatment

An adult male human suffering from onychomycosis of the left largetoenail was treated daily by topical application of a 10% topicalformulation of the invention containing KP-103. Additional components ofthe 10% topical formulation were alcohol, vitamin E, butylatedhydroxytoluene, cyclomethicone, diisopropyl alcohol, and C12-15 alkyllactates. Nail involvement at the initiation of treatment was 80% withonycholysis (separation of the nail plate from the nail bed) andthickening of subungual area. Following six months of treatment, thediseased proximal portion of the nail had grown out beyond the distalend of the nail plate (hyponychium) and was subsequently clipped off.There was no active fungal involvement of the nail plate, signs ofonycholysis or thickening of the subungual area, or nail involvementafter 6 months of treatment.

EXAMPLE 5 Additional Formulations of the Invention Containing KP-103

Several additional formulations of the invention were made containingidentical components, but in varying concentrations, as shown in Table4.

TABLE 4 10% 5% MATERIAL FUNCTION SOLUTION SOLUTION VEHICLE Alcoholvehicle 56.73 59.85 63.04 Cyclomethicone 5 wetting 12.30 13.00 13.67agent Diisopropyl non- 11.36 12.00 12.62 adipate volatile solvent C12-15non- 9.46 10.00 10.52 alkyl lactate volatile solvent KP-103 API 10.005.00 0.00 Vitamin E anti- 0.05 0.05 0.05 oxidant Butylated anti- 0.100.10 0.10 hydroxytoluene oxidant

While preferred embodiments of the invention have been described indetail, it will be apparent to those skilled in the art that thedisclosed embodiments may be modified. It is intended that suchmodifications be encompassed in the following claims. Therefore, theforegoing description is to be considered to be exemplary rather thanlimiting, and the scope of the invention is that defined by thefollowing claims.

The invention claimed is:
 1. A method for the treatment of onychomycosiscomprising topically applying to the surface of the nail of anindividual suffering from onychomycosis a pharmaceutical compositioncomprising ethanol, diisopropyl adipate, C12-15 alkyl lactate,cyclomethicone, and(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol;wherein the composition is formulated as a solution; wherein the ethanolis present in the composition at a concentration of at least 50% w/w;wherein the cyclomethicone is present in the composition at aconcentration less than 25% w/w; wherein the diisopropyl adipate andC12-15 alkyl lactate are present in the composition at a totalconcentration between 15 and 50% w/w; wherein the concentration of(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-olin the composition is about 10% w/w; and wherein the application of thecomposition is in an amount and for a time sufficient to ameliorate thesymptoms of the onychomycosis.
 2. The method of claim 1, wherein theconcentration of the cyclomethicone in the pharmaceutical composition isbetween 10% and 15% w/w.
 3. The method of claim 1, wherein thepharmaceutical composition does not comprise a polymeric film formingcompound.
 4. The method of claim 1, wherein: the concentration of theethanol in the pharmaceutical composition is at least 50% w/w; theconcentration of the cyclomethicone in the pharmaceutical composition isbetween 10% and 15% w/w; the combined concentration of the diisopropyladipate and the C12-15 alkyl lactate in the pharmaceutical compositionis between 15% and 50% w/w; and wherein the pharmaceutical compositiondoes not comprise a polymeric film forming compound.